The research goals included studies of 1) spatial and structural relationship of H-2 antigens and tumor-associated antigens, 2) immunogenicity of MHC products in murine serum and 3) molecular structures of Ia antigens in comparison with human DR antigens. Murine tumor cells in comparison to autologous normal cells display qualitative and/or quantitative changes in the expression of histocompatibility antigens. Tumor associated antigens of 6C3HED lymphoma cells are physically associated with H-2 antigens as shown by indirect immunoprecipitation of detergent produced cell extracts and analyses of the precipitates by SDS-PAGE. The immunogenicity of MHC products in murine serum was demonstrated by the production of xenoantibodies in rabbits. However, the determinants recognized by xenoantibodies are distinct from those reacting with H-2 and Ia alloantisera. The alpha-chains of Ia and DR antigens display a high degree of amino acid sequence homology as do their respective Beta-chains provided a gap is inserted in position 1 of the DR Beta chain. Comparison of the amino-terminal sequence reveals several differences between the Beta-chains of the Ia antigens of the two strains of mice. In contrast, no amino acid sequences are observed between the two murine alpha chains. Furthermore, tryptic peptide maps revealed several differences between the two Ia-Beta chains but not between their alpha-chains. These data suggest that the observed serologic polymorphism of murine Ia and human DR antigens may result from structural differences expressed on their respective Beta-chains.